Currently, over 25 million U.S. citizens have diabetes, including 20% of veterans in the VA system. With diabetes prevalence predicted to rise 35% by 2025, diabetic complications impose an ever-increasing burden on healthcare systems. One of the most common complications, diabetic retinopathy, is the leading cause of blindness in working age adults. In addition, early neuronal dysfunction in diabetic retinopathy occurs prior to clinically diagnosable pathology and is likely intimately related to other diabetic complications, for example, cognitive and motor deficits and microvascular changes in the brain. The continued increase in diabetic patient numbers and the complexity of their care underscores the urgent need to identify the earliest possible window for treatment. Our approach is to identify an earlier time point for intervention and develop clinically translatable treatments to target diabetic complications prior to obvious signs and symptoms. In this study, we will be using the Goto-Kakizaki rat model of Type II diabetes because approximately 90% of diabetic patients in the VA system are Type II. We hypothesize that: 1) early retinal deficits in diabetes will correlate with cerebral deficits and later stage retinal deficits, and 2) identifying the time course of early retinal deficits will allow us to introduce interventions prior to clinically relevant symptoms of diabetic retinopathy as well as cognitive and motor deficits. In the first specific aim, we will identify the temporal appearance of retinal dysfunction, using electroretinography to assess retinal function and optical coherence tomography to assess retinal structure, and test whether these defects correlate with cognitive dysfunction (y ?maze), motor dysfunction (rotarod), and later stage vascular pathology (acellular capillaries and pericyte loss). After determining the time course of these deficits, in the second specific aim, we will identify whether dopamine deficiency is a common mechanism underlying diabetic injury in the brain and retina. We will assess levels of dopamine and DOPAC (HPLC). After we have identified the temporal appearance of dopamine loss, we will implement L-DOPA treatment to reduce dopamine deficiency in diabetic rats. We will determine whether rats receiving treatment exhibit reduced dopamine deficiency and reduced retinal, cognitive, and motor dysfunction. In our third specific aim, we will determine whether exercise reduces dopamine deficiency and prevents the progression of visual and cerebral dysfunction in diabetes. The expected outcome of this study is that treating at the earliest signs of retinopathy in a rodent model of Type II diabetes will provide protection against diabetic damage in the brain and retina. This research can lead to the identification of a similar window for preclinical retinopathy treatment in diabetic patients, which would allow for greater treatment efficacy and prevention of future complications. If exercise and/or treatments that target dopamine protect against retinal and cerebral complications in diabetes, these findings would motivate the development of a human clinical trial. Overall, the motivation for this study is the need for a better understanding of early diabetic retinopathy with the long-term goal of developing treatments that delay or prevent vision loss and other complications in our Veterans and others with diabetes. The Atlanta VA has a large population of diabetic patients and is currently conducting research on the effects of exercise treatment on cognition and Parkinson's disease in VA patients, making this research project an excellent fit for the Center's goals and interests. This research will also provide valuable training to the postdoctoral candidate, which will enable her to become a successful and productive independent investigator in the field of diabetic retinopathy within the VA research environment.